These goals will be addressed
using behavioral, cognitive, fMRI, DTI, DTT and neuro-pathologic
studies of:

Infant
Siblings

First-Diagnosed Toddlers with Autism

Children,
Adolescents and Adults with and without Autism

Project I focuses on understanding the
earliest manifestations of autism and the development of earlier
diagnostic tools. It also focuses on information processing mechanisms
underlying social and cognitive symptoms. The center of this proposal is on one of the most basic and critical
aspects of information processing-categorization. The term
categorization is used in a broad sense to mean not only the grouping of
similar objects, but also a process basic to our core perceptual
recognition abilities. Categorization is a process that begins within
the first few months of life. Infants quickly begin to categorize their
world, significantly reducing demands on memory. Once the infant can
categorize and have a central representation of similar objects such as
dogs, it is not necessary to remember every encountered instance unless
the instance is unusual. The ability to categorize is also critical to
language development, and most theories assume it is a prerequisite for
learning words. Categorizing or prototyping is also central to f
recognition abilities and problem solving. This project will extend our
current research on high functioning children and adults with autism (HFA)
on processing categorical information about objects and facial
information including gender, emotional expression, recognition and
attractiveness. Studies will take a more in-depth look at the mechanisms that underlie
development of categorical expertise. Extensions of this research will look
into understanding individual differences in performance of HFA
participants, and will provide important behavioral indices of autism
that will be used by Projects II, III and IV as they attempt to
characterize the neuro-anatomy of autism as reflected in brain structure
and connectivity. Importantly, this research will be extended to two
populations critical to our understanding of autism spectrum disorders (ASD)
including its origin, early diagnosis, and the development of early
intervention strategies. First, this project will longitudinally study a
group of 6- to 16- month old infant siblings of older children diagnosed
with autism. Second, the project will study a group of newly diagnosed
ASD toddlers that are low functioning. Both of these populations will be
tested with nonverbal methodologies originally designed for studying
typically developing infants and toddlers. These methods will allow us
to look at critical early information processing abilities such as
attention, memory, and categorization. These methods represent
well-designed experimental procedures that could easily be translated to
clinical practice for early diagnosis if results support their use.
These methods allow us to study underlying information processes
currently not addressed by more standard observation studies of at risk
infants. These basic information-processing mechanisms are more
effective targets for changing outcome than behavior. This project will directly address the Autism
Research Matrix goal
#19 of developing “indices of risk for the development of autism” and #4
characterizing the autism phoneme.

Project II: Disturbances of Affective Contact:
Development of Brain Mechanisms for Emotion ProcessingProject II focuses on elucidating emotion
processing mechanisms and the maturational disturbances from childhood
through adulthood; these studies will clarify how individual with autism
experience, understand and regulate emotion, and will also examine their
self-awareness of emotion. Genetic modifiers of emotionality will also
be determined. Kanner’s (1943) original characterization of autism as a "Disturbance of
Affective Contact" encompassed the lack of the capacity to connect from
an early age emotionally to people, reflecting broad impairments in the
experience, perception, regulation, and expression of emotion as well as
in synchronizing and sharing it to form relationships. Since then,
researchers have started to characterize these deficits at the
behavioral level. In addition, a few studies have begun to explore the
brain mechanisms underlying the deficits in adults with autism. Despite
these important efforts, the characterization of the development of
brain mechanisms for emotion processing remains a critical and largely
unmet challenge, with few studies exploring this in individuals with and
without autism throughout childhood. Further studies are required to examine the relationship between the
development of emotion processing and that of underlying neural systems,
particularly sub-cortical, temporal, and prefrontal cortical structures
and their interactions. Such studies will inform the understanding of
the neural bases of atypical emotional development in children with
autism and of normal emotional development in children without autism,
and the results will aid the development of earlier and better
behavioral interventions and management for children and adults with
autism. In this application, we propose to study samples of 6- to 11-year-old
children with and without autism and adults with and without autism
using a multiple methodology approach to characterize the development of
brain mechanisms for emotion processing. We will investigate the
perception, understanding, experience, and expression of emotion using
eye tracking and behavioral measurements. We will also chart the
functional development of the underlying neural substrates for emotion
processing using functional magnetic resonance imaging (fMRI) and
paradigms designed to probe atypical patterns in autism both in the
functioning of specific brain regions and in the functional connectivity
between key emotional brain structures. Finally, we will adopt an
imaging genetics approach to examine gene-brain-behavior interactions in
shaping the development of the emotional brain and as inter-individual
modifiers of behavioral expression. Specifically, we will examine the
role of the 5-HTTLPR S allele in the development of amygdala dysfunction
and in reduced functional connectivity between limbic and prefrontal
structures in autism. Research on the behavioral and neural mechanisms underlying the
development of emotion processing deficits in autism, as proposed in
this application, will provide important new insights into the
development of the emotional brain in autism. It will also provide
behavioral and brain phenotypes for genetics studies to investigate
important genetic modifiers of behavioral expression that may be
amenable to rational pharmacotherapy. Improved understanding of the
behavioral, cognitive, and neural mechanisms of emotional processing in
autism will improve the recognition and treatment of the profound
emotional immaturity in ASD that is associated with problematic behavior
at all ages and contributes to poor function in adulthood. This research addresses Autism Research Matrix
goals
# 16, 19, 22, 23, 26, 31, and 34.

Project III focuses
on understanding disturbances in functional brain connectivity that
underlie the impaired processing of information and in turn the
cognitive and behavioral impairments in autism. The project also
includes innovation machine-learning studies of how the brain identifies
and categorizes words and computational modeling of cortical function.
The overriding
aim of this project is to relate the major symptoms of autism to
abnormalities in their neural substrates, providing a neural
systems-level analysis of autism, and focusing on neural systems
connectivity. The primary method will be to perform fMRI studies of
several different types of thinking to obtain information about
underlying brain function, and to simultaneously acquire information
about the size and integrity of brain tissues. The fMRI studies will
provide information about cortical activation, but also about functional
connectivity or the synchronization of the activation between areas.
The project has developed the beginnings of a theory proposing that
autism is marked by disordered connectivity among regions, particularly
affecting the connectivity between frontal areas and more posterior
areas. The connectivity framework is being used to formulate and test
hypotheses and then integrate the new findings into a coherent theory.
The new studies will deepen and broaden the understanding of the
underlying neural disorder. The deepening will include the integration
of several imaging modalities, so that the connectivity can be
understood at more levels and in more detail. The broadening will
consist of examining a wider range of tasks, to include conceptual
comprehension, high-level perceptual tasks, and social tasks. This
broadening is essential for determining the generality or specificity of
the brain function characteristics of autism. The specifics aims are:

To characterize
brain function in the processing of higher conceptual levels of
language comprehension, visual cognition, and dynamic social
cognition.

To characterize
the semantic representation of single words in individual
participants with autism applying innovative machine learning
techniques to fMRI data. Autism as a disturbance in

To relate
functional characteristics of the brain to anatomical
characteristics at the individual participant level.

To further
develop the theory of disordered connectivity in autism, integrating
functional (fMRI) and anatomical (MRI and DTI) characteristics of
autism and using computational modeling as a theory-building tool.

This research will continue to build an understanding of the
relationship between the behavioral impairments that characterize autism
and their neural basis. The connectivity model for autism advanced on
the basis of this research has significantly influenced the field and
validates the complex information processing development by Minshew,
Goldstein and Williams. The combined model is proving to be promising in
altering conceptualizations of autism and opening the way for new
intervention methods (see deception learning for example). This research addresses Autism Research Matrix
Goals
# 2, 6, 22, 23, 26, and 34.